Abstract Background Despite improved outcomes with programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors (ICI) in renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC), most patients develop resistance. Preclinical data demonstrate that Janus kinase inhibition (JAKi) restores T cell cytokine production and proliferation, potentiating ICI activity, with ruxolitinib plus ICI demonstrating superior tumor control across multiple murine models. Ruxolitinib may also reprogram immunosuppressive myeloid populations within the tumor microenvironment. In an investigator-initiated trial (NCT03681561), 53% of patients with relapsed/refractory Hodgkin’s Lymphoma previously failing anti-PD-1 therapy responded to ruxolitinib plus nivolumab, including 6 complete responses. High response rates were also observed with JAKi plus anti-PD-1 in NSCLC (NCT03425006). We aim to investigate whether combining ruxolitinib with anti-PD-1 therapy can overcome resistance in solid tumors. Methods This prospective, open-label, single-arm phase 1b study evaluates ruxolitinib plus retifanlimab in patients with advanced clear cell RCC or NSCLC progressing on prior PD-1/PD-L1 therapy. Patients must have measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate organ function. Key exclusions: prior JAKi, >1 prior line of PD-1/PD-L1 therapy, primary progression on prior ICI, or unresolved immune-related adverse event (>grade 1). A 3 + 3 dose escalation design evaluates ruxolitinib 15 mg and 20 mg twice daily with fixed retifanlimab 500mg intravenously (IV) every 4 weeks, followed by dose expansion. Treatment continues until progression, toxicity, or withdrawal. The primary objective is determining the recommended phase 2 dose (RP2D). Secondary objectives include objective response rate, duration of response, radiographic progression-free survival, overall survival, and safety. To further interrogate mechanisms of response and resistance, correlative studies evaluating tumor microenvironment, immune cell composition, and molecular profiling are ongoing. A Simon’s two-stage design is utilized for testing the null hypothesis (true response rate 10%) against an alternative of 30%, rejecting null if ≥ 6 responses occur in 25 participants (α = 0.05, power 80%). Assuming a dropout rate of 5%, we will target a minimum enrollment of 36 and maximum enrollment of 42 participants to ensure a maximum of 40 evaluable participants on the trial. The standard survival analysis will be conducted for the time-to-event endpoints. The study is activated at the University of California San Diego and is currently open to accrual. Clinical Trial Information: NCT07219576. Results Resistance to PD-1/PD-L1 blockade is a major unmet need in RCC and NSCLC, with few effective options after progression on frontline immunotherapy. PRISM tests a mechanistically rational combination, ruxolitinib to reverse chronic interferon-driven T cell dysfunction and immunosuppressive myeloid skewing, paired with retifanlimab to sustain antitumor T cell activity. Integrated correlative studies aim to identify biomarkers of response to guide patient selection. Our vision is to establish JAK inhibition as a tractable strategy for restoring checkpoint sensitivity across solid tumors, providing the foundation for a biomarker-driven randomized phase 2 trial in checkpoint-refractory disease. Conclusions NA

INTRODUCTION AND OBJECTIVE:Subcentimeter pulmonary nodules (SPN) found in clinical stage I (CS I) seminoma may be early pulmonary metastases or incidental, benign entities that may lead to patient anxiety and overtreatment. This study aims to demonstrate the incidence and natural history of SPN in CS I seminoma patients. METHODS:A retrospective study reviewing the medical records of CS I seminoma patients treated at UC San Diego Health between 2003 and 2023. Data collection included demographics, serum tumor markers (STM), imaging reports, pathologic findings, treatment records, and records of disease relapse. We described SPN as a finding either from a chest X-ray (CXR) or a computed tomography (CT) scan of the chest at the time of seminoma diagnosis, with a size <1cm. The incidence of SPN and relationship with disease relapse was explored. RESULTS:79 patients with CS I seminoma were included in the study, and mean follow-up time was 40 months. Our general practice is to observe all patients with stage I seminoma except under extenuating circumstances. Among them, 21 patients were found to have SPN, all which were diagnosed on CT scan of chest, resulting in an incidence rate of 26.6%. Notably, there was no statistically significant difference in the occurrence of SPN between patients with CS IA and CS IB (27.9% and 22.2%, respectively, P = 0.227). Four patients (5%) experienced disease relapse. None of the patients that had a relapse had an incidental subcentimeter nodules. Six patients received adjuvant chemotherapy (CMT); 1 patient had a pulmonary nodule and did not relapse; 1 patient experienced disease relapse without nodule. 10 patients underwent adjuvant radiation (RT), with no recurrence observed despite 4 of them having nodules. Additionally, 5 patients with nodules received adjuvant CMT or RT; none recurred. 16 patients with nodules were under surveillance, none recurred. CONCLUSIONS:The incidence of SPN in CS I seminoma patient is high. Subcentimeter nodules do not appear to be related to risk of disease relapse. Our findings suggest that patients with CS I seminoma and incidental SPN can be counseled that this is a common, clinically insignificant finding. Further validation in a larger population is necessary.

AbstractWe sought to evaluate the genomic and transcriptomic landscapes in primary and metastatic germ cell tumors (GCTs; N = 138) to uncover factors that drive cisplatin resistance. Prevalence was calculated for platinum-resistant alterations (PRAs; KRAS, TP53, and KIT mutations, and MDM2 amplification) and high copy number amplifications (CNA ≥ 6 copies). Tumors were designated as chemo-naïve (PreC, N = 66) or post-chemotherapy (PostC, N = 17). A transcriptomic signature associated with platinum sensitivity (PSS, high suggests increased sensitivity) was applied. KIT mutations were observed in 14.5% of primary versus 1.8% of met and 0% of lymph. TP53 mutations were identified in 10% of primary GCTs versus 17% of met and 16.7% of lymph. MDM2 CNAs were similar between sites. PRA-positive PreC GCTs had significantly lower average PSS scores compared to PRA-negative tumors. Lower PSS scores in chemo-naïve tumors were associated with PRAs, suggesting a potential mechanism for platinum resistance.

Purpose of review This review highlights the importance of addressing testicular cancer metastasizing beyond the retroperitoneum, focusing on multidisciplinary approaches and advances in treatment. Recent findings Recent literature emphasizes on the evolving landscape of metastasis-directed therapy, including surgical interventions, chemotherapy regimens, and radiation therapy. The effectiveness of these treatments varies depending on the site of metastasis, with various approaches improving survival rates and quality of life for patients. We divide our review in an organ-specific manner and focus on chemotherapeutic, surgical, and radiation therapy approaches pertaining to each site of metastasis. Summary Our review suggests the pressing need for continued research to refine and personalize treatment strategies. These efforts are important for enhancing clinical practice, ultimately leading to better outcomes for patients with metastatic testicular cancer.

You have accessJournal of UrologyPenile & Testicular Cancer I (MP01)1 May 2024MP01-16 MOLECULAR DRIVERS OF ORGANOTROPISM AND CISPLATIN RESISTANCE IN GERM CELL TUMORS Margaret F. Meagher, Yun Cheng Sawa, Liwei Jia, Frederick Millard, Harris Krause, Alex Farrell, Andrew Elliott, John Lafin, Christina Jamieson, Emmanuel Antonarakis, Anishka D'Souza, Krinio Giannikou, James Amatruda, Siamak Daneshmand, Rana McKay, Matthew Oberly, Chadi Nabhan, and Aditya Bagrodia Margaret F. MeagherMargaret F. Meagher , Yun Cheng SawaYun Cheng Sawa , Liwei JiaLiwei Jia , Frederick MillardFrederick Millard , Harris KrauseHarris Krause , Alex FarrellAlex Farrell , Andrew ElliottAndrew Elliott , John LafinJohn Lafin , Christina JamiesonChristina Jamieson , Emmanuel AntonarakisEmmanuel Antonarakis , Anishka D'SouzaAnishka D'Souza , Krinio GiannikouKrinio Giannikou , James AmatrudaJames Amatruda , Siamak DaneshmandSiamak Daneshmand , Rana McKayRana McKay , Matthew OberlyMatthew Oberly , Chadi NabhanChadi Nabhan , and Aditya BagrodiaAditya Bagrodia View All Author Informationhttps://doi.org/10.1097/01.JU.0001008660.87408.90.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Treatment failure in germ cell tumors (GCTs) can be driven by platinum resistance. We sought to characterize patterns of metastasis in germ cell tumors, and associate platinum resistance with primary versus metastatic GCTs. METHODS: GCT samples (N=138) collected between 2010 and 2022 were analyzed at Caris Life Sciences. A primary tumor (N=65) was defined as collected from the annotated primary. Metastatic tumors (N=73) were defined as any non-primary tumor biopsied from non-lymph node anatomic sites. Next-generation sequencing of DNA and RNA was performed. Frequency of platinum resistant alterations (PRAs: KRAS, TP53, KIT, MDM2) were compared between primary and metastatic sites. RESULTS: Primary tumor sites included: 7 intracranial (10.8%), 5 mediastinal (7.7%), 16 ovarian (24.6%), 37 testicular (56.9%). Metastatic sites included: 2 bone (2.7%), 11 brain (15.1%), 6 liver (8.2%), 5 lung (6.8%), 14 lymph node (19.2%), 4 mediastinum (5.5%), 12 peritoneum (16.4%), 1 testicle (1.4%), 18 (24.7%) non-bone/brain/liver visceral sites. Metastatic testicular primary accounted for 49 (67.1%) of metastatic specimens. We did note a significantly greater prevalence of KIT-Mt in primary (14.5%) versus metastatic (1.8%) tumors (p<0.05). Conversely, TP-53-Mt had greater representation in the metastatic (17%) versus primary (10%) setting (p<0.05). No differences with respect to alteration patterns were noted between testicular primary and metastatic testicular primary (p>0.05). CONCLUSIONS: We present a large cohort of primary and metastatic germ cell tumors. We noted differing prevalence of PRAs between primary and metastatic sites, highlighting a potential mechanism by which cisplatin-based regimens fail. Source of Funding: N/A © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e8 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Margaret F. Meagher More articles by this author Yun Cheng Sawa More articles by this author Liwei Jia More articles by this author Frederick Millard More articles by this author Harris Krause More articles by this author Alex Farrell More articles by this author Andrew Elliott More articles by this author John Lafin More articles by this author Christina Jamieson More articles by this author Emmanuel Antonarakis More articles by this author Anishka D'Souza More articles by this author Krinio Giannikou More articles by this author James Amatruda More articles by this author Siamak Daneshmand More articles by this author Rana McKay More articles by this author Matthew Oberly More articles by this author Chadi Nabhan More articles by this author Aditya Bagrodia More articles by this author Expand All Advertisement PDF downloadLoading ...

A 41 -year -old man presented to his primary care physician with a 1 -month history of left neck adenopathy in the context of a history of nonseminomatous germ cell tumors (NSGCTs). In 2011, the patient was treated for stage IB (T2N0M0S0) right -sided NSGCTs of the testis, which were 95% embryonal and 5% yolk sac tumors. He underwent a right radical orchiectomy and was followed until 2022 without recurrence. In the work -up for his adenopathy, laboratory results for human chorionic gonadotropin, lactate dehydrogenase, and alpha-fetoprotein were normal. CT scans confirmed clustered enlarged lymph nodes in the left lower spinal accessory posterior triangle, enlarged left lower neck lymph nodes, and several foci of enlarged left retroperitoneal periaortic lymph nodes. Fine needle aspiration of a left neck lymph node identifi ed malignant tumor cells. A left neck dissection showed embryonal carcinoma in 12 of 28 nodes. Immunostaining showed the tumor cells were positive for SALL4 and CD30 but negative for CD117. This patient likely had a contralateral late relapse of his original right NSGCT after 11 years of remission. The patient's original cancer was on the right side, with recurrence surrounding the aorta on the contralateral side, representing an atypical pattern of spread.

Supplementary data - Table S1. Incidence of all adverse events occurring in {greater than or equal to}15% of patients as well as grade 3 to 5 adverse events* Figure S1. Study schematic. Figure S2. Time-to-PSA progression* from testosterone recovery to {greater than or equal to}175 ng/dL. Figure S3. Time-to-testosterone recovery. Figure S4. Time-to-next anti-cancer intervention in both arms. Figure S5. Comparison of humoral antigen spread at week 2 between STAND versus IMPACT and STAMP. Figure S6. Sipuleucel-T parameters: (A) TNC count, (B) APC count, and (C) APC activation in autologous peripheral blood mononuclear cells after ex vivo PA2024 activation. Figure S7. Comparison of APC activation (CD54+ upregulation) between STAND and IMPACT.

10534 Background: With the growing indications for germline testing in prostate cancer (PCa), there is accumulating evidence that African American and Hispanic men with PCa are significantly under-tested compared to non-Hispanic white (NHW) men. Given this, little is known about the pathogenic germline variant landscape in Hispanic men with PCa. Methods: This was a retrospective cohort analysis of 17,256 men with PCa who underwent diagnostic germline testing through a commercial laboratory (Invitae) from 2015-2020. Self-identified Hispanic and NHW men were selected for comparative analysis. The primary endpoint was the rate of pathogenic/likely pathogenic (PLP) germline alterations in Hispanic men among 25 genes associated with PCa. Secondary endpoints included comparison of PLP rates in Hispanic vs NHW men, the rate of specific PLP alterations, and the rate of variants of uncertain significance (VUS). Fisher’s exact test was used to compare germline alteration rates for significance. Results: We identified 508 Hispanic and 12,542 NHW men with PCa who underwent testing during the study period. Median age at the time of testing was 69 vs 67 years in Hispanic vs NHW cohorts. A family history of PCa was reported in 21.1% (N=108) vs 27.3% (N=3428) in the Hispanic vs NHW cohorts, respectively (p=0.002). The PLP alteration rate was 7.1% in the Hispanic cohort and this rate was numerically lower but not significantly different when compared to the NHW cohort (9.7%) (p=0.058). A significantly higher rate of VUS was seen in the Hispanic cohort (Table). The four most frequently detected genes with PLP alterations in both cohorts were ATM, BRCA1, BRCA2, and CHEK2. Only the rate of CHEK2 alterations was significantly different between cohorts among all 25 genes analyzed (Table). Conclusions: In this analysis, the PLP alteration rate among Hispanic men was 7.1%, a much higher rate than has been previously reported, and the germline genomic landscape was similar to that of NHW men. The VUS rate was significantly higher among Hispanic men, a known consequence of under-testing among minority populations.These data support germline testing in Hispanic men with prostate cancer and emphasize the importance of improving testing rates.[Table: see text]

150 Background: Little is known about the clinical course of patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) who harbor alterations in the homologous recombination repair (HRR) pathway. Here, we examine the outcomes of men with mHSPC with HRR alterations. Methods: Single center, retrospective analysis of men with mHSPC who underwent next generation sequencing from 2015-2020. The primary endpoint was to assess the time from diagnosis of mHSPC to onset of castrate resistance (mCRPC), as defined by PCWG3 criteria, in pts with HRR alterations vs wild type (WT). Both somatic and germline HRR alterations were permitted. Univariate and multivariate Cox regression were used to assess the effect of HRR alterations on time to mCRPC. Secondary endpoints included time to mCRPC stratified by HRR gene and time to treatment failure (TTF) in HRR altered vs WT pts, stratified by therapy. Results: We identified 151 men with mHSPC for the study. Median age was 66 years and 62% (n = 93) had de novo metastatic disease. 25% (n = 37) had HRR alterations detected and the most common alterations were in BRCA2 (n = 15), ATM (n = 10), CDK12 (n = 7). 78.4% (n = 29) of alterations were somatic and 13.5% (n = 5) of pts had co-alterations in 2 HRR genes. Time to mCRPC was significantly decreased in pts with HRR alterations vs WT (12.7 vs 16.1 mos, HR- 1.95, p- 0.02). In multivariate analysis, the effect of HRR alterations on time to mCRPC remained statistically significant when adjusting for age, mHSPC therapy, presence of visceral metastases, and PSA (adjusted HR- 1.69, p-0.02). Stratified by individual HRR gene, pts with BRCA2, CDK12, or co-occurring alterations had significantly decreased time to mCRPC compared to other HRR alterations (Table). In terms of mHSPC therapy, 45.7% were treated with ADT alone, 27.8% with an androgen receptor signaling inhibitor (ARSI), and 26.5% with docetaxel. TTF was inferior in HRR altered vs WT pts (10.8 vs 13.8 mos, p-0.004, HR- 1.84). Stratified by therapy, TTF was inferior in HRR altered vs WT pts treated with ADT alone (8.9 vs 13.3 mos, p- 0.019, HR-1.94) and there was no significant difference in TTF in HRR altered vs WT pts treated with either the addition of an ARSI or docetaxel. Conclusions: HRR alterations are associated with worsened outcomes in mHSPC patients. Given the established role of PARP inhibitors in mCRPC, these data highlight an opportunity to explore the use of PARP inhibitors in mHSPC to potentially improve outcomes. [Table: see text]

Background Sipuleucel-T (sip-T) is a Food and Drug Administration (FDA)-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). We hypothesized that combining sip-T with interleukin (IL)-7, a homeostatic cytokine that enhances both B and T cell development and proliferation, would augment and prolong antigen-specific immune responses against both PA2024 (the immunogen for sip-T) and prostatic acid phosphatase (PAP). Methods Fifty-four patients with mCRPC treated with sip-T were subsequently enrolled and randomized 1:1 into observation (n=26) or IL-7 (n=28) arms of a phase II clinical trial ( NCT01881867 ). Recombinant human (rh) IL-7 (CYT107) was given weekly×4. Immune responses were evaluated using flow cytometry, mass cytometry (CyTOF), interferon (IFN)-γ ELISpot, 3 H-thymidine incorporation, and ELISA. Results Treatment with rhIL-7 was well tolerated. For the rhIL-7-treated, but not observation group, statistically significant lymphocyte subset expansion was found, with 2.3–2.6-fold increases in CD4+T, CD8+T, and CD56 bright NK cells at week 6 compared with baseline. No significant differences in PA2024 or PAP-specific T cell responses measured by IFN-γ ELISpot assay were found between rhIL-7 and observation groups. However, antigen-specific T cell proliferative responses and humoral IgG and IgG/IgM responses significantly increased over time in the rhIL-7-treated group only. CyTOF analyses revealed pleiotropic effects of rhIL-7 on lymphocyte subsets, including increases in CD137 and intracellular IL-2 and IFN-γ expression. While not powered to detect clinical outcomes, we found that 31% of patients in the rhIL-7 group had prostate specific antigen (PSA) doubling times of >6 months, compared with 14% in the observation group. Conclusions Treatment with rhIL-7 led to a significant expansion of CD4+ and CD8+ T cells, and CD56 bright natural killer (NK) cells compared with observation after treatment with sip-T. The rhIL-7 treatment also led to improved antigen-specific humoral and T cell proliferative responses over time as well as to increased expression of activation markers and beneficial cytokines. This is the first study to evaluate the use of rhIL-7 after sip-T in patients with mCRPC and demonstrates encouraging results for combination approaches to augment beneficial immune responses.

Background: Little is known about the prevalence of germline alterations in Hispanic men with prostate cancer (PC). Here, we examine the rates of germline alterations in Hispanic men with PC, compare these rates to non-Hispanic white men, and examine factors associated with clinicians offering testing. Methods: Single center, retrospective analysis of patients (pts) with PC who self-identify as Hispanic and meet the NCCN criteria for germline testing. Pts who consented for testing underwent a commercial multigene germline assay. Among those tested, the proportion of pathogenic alterations and variants of uncertain significance (VUS) were computed in 20 genes associated with germline alterations in PC. This was compared to non-Hispanic white (NHW) pts who also underwent germline testing. Multivariate logistic regression was performed to assess clinical and demographic factors associated with clinicians offering germline testing and/or genetics referral. Results: We identified 136 Hispanic men with PC eligible for germline testing between 2018-2020. 26.1% (n=34) of pts underwent germline testing and among those tested, 14.7% (n=5/34) had a pathogenic alteration detected. Median age of the cohort was 70 years and 46.3% (n=63) had metastatic disease. Spanish was the primary language for 50% (n=68) and 14.0% (n=19) of pts had at least 1 first-degree relative with PC. Alterations were detected in ATM (n=2), CHEK2 (n=1), MSH2 (n=1), MSH6 (n=1). When stratified by disease status, the rate of pathogenic alterations was 7.7% (n=1/13) in localized and 19.0% (n=4/21) in metastatic disease. When compared to NHW pts who underwent testing (n=139), the rate of pathogenic alterations was not significantly different (14.7% in Hispanic vs 12.2% in NWH, p=0.77). The rate of VUS in Hispanic pts was significantly higher than NHW pts (20.6% in Hispanic vs 7.2% in NWH, p=0.047). In a multivariate model examining the factors associated with receipt of testing in Hispanic men (Table), the presence of metastatic disease and a family history of PC were positively associated with testing. Spanish as a primary language was negatively associated with testing. Age was not a significant predictor. Conclusions: Among Hispanic men who underwent germline testing, there was a similar rate of pathogenic germline alterations compared to NHW men. Among Hispanic men, primary Spanish speakers appear to have lower rates of germline testing. Bilingual strategies are needed to improve rates of testing to ensure equity in germline testing for all patients. [Table: see text]

In advanced prostate cancer, circulating tumor (ctDNA) has been increasingly used for genomic sequencing. We examined the real-world use of commercial ctDNA assays among a cohort of patients with metastatic castrate resistant prostate cancer (mCRPC) and assessed the ctDNA genomic landscape, rate of actionable alterations, and the correlation of ctDNA characteristics with survival. We found that ctDNA detected pathogenic alterations in most patients and the number of detected alterations was strongly associated with inferior overall survival. Background: There has been considerable interest in ctDNA next generation sequencing platforms to assess genomic alterations in mCRPC given its accessibility and identification of temporal genomic data. Patientsand Methods: In this retrospective analysis, we analyzed 63 patients who underwent ctDNA genomic profiling during their mCRPC disease course using a CLIA-certified commercial assay. The primary objective was to assess the feasibility of commercial ctDNA analysis in a real world mCRPC cohort. Key secondary objectives included assessment of the landscape of pathogenic ctDNA alterations and the prognostic significance of ctDNA detection on overall survival (OS). Results: Among the cohort, at the time of ctDNA collection, median age was 70 years, and 47.6% (N = 30/63) had bone-only metastases. ctDNA was detected in the majority of patients with at least 1 pathogenic alteration detected in 90.5% (N = 57/63) of individuals. The most common alterations detected were in AR, TP53, and PIK3CA. Actionable alterations with FDA-approved therapies were found in 15.8% (N = 10) of the cohort. The presence of <= 1 versus > 1 alteration on ctDNA analysis was strongly associated with inferior OS with a median OS of 26.1 versus 8.8 months, respectively (HR = 7.0, 95% CI, 2.2-23.1, P < .001). In multivariate analysis, the number of detected alterations remained a significant predictor for OS. Lastly, there was weak correlation between Prostate-Specific Antigen (PSA), and ctDNA characteristics. Conclusion: ctDNA is a viable next generation sequencing (NGS) platform in mCRPC and can be utilized to identify actionable alterations. The presence and extent of ctDNA alterations appear to be prognostic of OS in mCRPC. (C) 2021 Elsevier Inc. All rights reserved.

110 Background: Given the technical limitations of obtaining tissue next-generation sequencing, there has been interest in blood ctDNA to assess genomic alterations in mCRPC. We examined the genomic landscape and prognostic significance of ctDNA in mCRPC. Methods: Single center retrospective analysis of mCRPC patients who underwent ctDNA genomic profiling using Guardant360. Overall survival (OS) and time to progression (TTP) were examined and stratified by the presence of tumor suppressor mutations (p53, PTEN, Rb), androgen receptor (AR) amplification or mutation, number of genomic alterations, and highest allelic fraction of detected mutations. Results: At the time of ctDNA collection, all patients (n=46) had mCRPC with bone metastases present in 100% of patients and visceral metastases present in 17.3%. Median age at ctDNA collection was 71 years, median time from CRPC diagnosis to ctDNA was 13 months (range 0-45), and median follow-up time from CRPC diagnosis was 17.5 months (4-40). The most common alterations present were TP53 mutation (41.3%), AR amplification (30.4%), and CDK6 amplification (21.7%). Actionable mutations were detected in BRCA1 (4.3%), BRCA2 (4.3%), ATM (2.2%), and PMS2 (2.2%). The median number of genomic alterations was 2 (0-8) and the median ctDNA allelic fraction was 4.6% (0-86.9%). Median OS of the cohort was 36 months. The presence of a tumor suppressor mutation, > 2 genomic alterations, and >5% mutation allelic fraction was associated with inferior OS (Table). In terms of time to progression on 1st line abiraterone or enzalutamide, the presence of an AR amplification or mutation was associated with significantly worse median TTP of 6.9 vs 13.5 months ( p- 0.015). Conclusions: ctDNA is frequently detected in mCRPC; and the type, number and frequency of alterations are potentially prognostic of OS in mCRPC. Ongoing studies are needed to assess concordance of ctDNA with tissue NGS and the predictability of ctDNA.[Table: see text]

You have accessJournal of UrologyProstate Cancer: Markers II (PD52)1 Apr 2020PD52-12 ANALYSIS OF THE PROGNOSTIC SIGNIFICANCE OF CIRCULATING TUMOR DNA (CTDNA) IN METASTATIC CASTRATE RESISTANT PROSTATE CANCER (MCRPC) Justin Shaya*, J. Michael Randall, Frederick Millard, Razelle Kurzrock, J. Kellogg Parsons, Pablo Tamayo, and Rana McKay Justin Shaya*Justin Shaya* More articles by this author , J. Michael RandallJ. Michael Randall More articles by this author , Frederick MillardFrederick Millard More articles by this author , Razelle KurzrockRazelle Kurzrock More articles by this author , J. Kellogg ParsonsJ. Kellogg Parsons More articles by this author , Pablo TamayoPablo Tamayo More articles by this author , and Rana McKayRana McKay More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000954.012AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Given the technical limitations of obtaining tissue next-generation sequencing, there has been considerable interest in blood ctDNA to assess genomic alterations in mCRPC. We examined the genomic landscape and prognostic significance of ctDNA in mCRPC. METHODS: Single center retrospective analysis of mCRPC patients who underwent ctDNA genomic profiling using Guardant360. Overall survival (OS) and time to progression (TTP) were examined and stratified by the presence of tumor suppressor mutations (p53, PTEN, Rb), androgen receptor (AR) amplification or mutation, number of genomic alterations, and highest allelic fraction of detected mutations. RESULTS: At the time of ctDNA collection, all patients (n=46) had mCRPC with bone metastases present in 100% of patients and visceral metastases present in 17.3%. Median age at ctDNA collection was 71 years, median time from CRPC diagnosis to ctDNA was 13 months (range 0-45), and median follow-up time from CRPC diagnosis was 17.5 months (4-40). The most common alterations present were TP53 mutation (41.3%), AR amplification (30.4%), and CDK6 amplification (21.7%). Actionable mutations were detected in BRCA1 (4.3%), BRCA2 (4.3%), ATM (2.2%), and PMS2 (2.2%). The median number of genomic alterations was 2 (0-8) and the median ctDNA allelic fraction was 4.6% (0-86.9%). Median OS of the cohort was 36 months. The presence of a tumor suppressor mutation, > 2 genomic alterations, and >5% mutation allelic frequency was associated with inferior OS (Table 1). In terms of time to progression on 1st line abiraterone or enzalutamide, the presence of an AR amplification or mutation was associated with significantly worse TTP of 6.9 months vs 13.5 months (p-0.015). Lastly, median PSA of the cohort was 73.5 and PSA was weakly associated with both ctDNA allelic fraction (r2-0.064, p-0.01) and number of genomic alterations (r2-0.088, p<0.001) by Pearson correlation. CONCLUSIONS: ctDNA is frequently detected in mCRPC; and the type, number and frequency of alterations are potentially prognostic of OS in mCRPC. Ongoing studies are needed to assess concordance of ctDNA with tissue NGS and the predictability of ctDNA. Source of Funding: None. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1094-e1095 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Justin Shaya* More articles by this author J. Michael Randall More articles by this author Frederick Millard More articles by this author Razelle Kurzrock More articles by this author J. Kellogg Parsons More articles by this author Pablo Tamayo More articles by this author Rana McKay More articles by this author Expand All Advertisement PDF downloadLoading ...

Neoadjuvant sunitinib may facilitate partial nephrectomy in imperative indications. A retrospective comparison was performed of outcomes in patients who received neoadjuvant sunitinib before nephrectomy and inferior vena caval thrombectomy; results indicated that neoadjuvant sunitinib was associated with a reduction in primary tumor and thrombus size and improved survival. These findings represent the largest single-agent series and the first reported comparison. Background: We analyzed outcomes of neoadjuvant sunitinib in patients with renal-cell carcinoma (RCC) and inferior vena caval (IVC) tumor and compared outcomes to patients who did not undergo neoadjuvant therapy before surgery. Patients and Methods: We performed a multicenter retrospective comparison of RCC patients with IVC tumor who underwent neoadjuvant sunitinib before surgery versus those who did not. Response to sunitinib was defined by Response Evaluation Criteria in Solid Tumors (RECIST). Primary outcome was cancer-specific survival. Secondary outcomes included overall survival. Multivariate analysis was performed to identify risk factors associated with primary and secondary outcomes. Kaplan-Meier analysis compared survival in neoadjuvant and primary surgery groups. Results: Data of 53 patients were analyzed (19 neoadjuvant sunitinib, 34 primary surgery; median follow-up, 58 months). Eighteen (9 in each group, P = .143) had metastatic RCC. There was no difference in IVC tumor level between the 2 groups (P = .76). After neoadjuvant sunitinib, median primary tumor decreased size from 8.1 to 6.8 cm, and IVC tumor decreased by 1.3 cm. IVC tumor level decreased in 8 (42.1%) of 19 and was stable in 10 (52.6%) of 19; 5 (26.3%) of 19 experienced partial response. Similar proportions of patients underwent robot-assisted or minimally invasive approaches (P = .351), and no differences were noted in complications (P = .194). Multivariate analysis showed neoadjuvant sunitinib was associated with improved cancer-specific survival (odds ratio = 3.28; P = .021). Kaplan-Meier analysis demonstrated significantly longer median cancer-specific survival (72 vs. 38 months, P = .023) for neoadjuvant sunitinib. Conclusion: Neoadjuvant sunitinib was associated with a reduction in primary tumor and thrombus size as well as improved survival. Further investigation is needed to determine the utility of neoadjuvant sunitinib in RCC with IVC tumor. (C) 2019 Elsevier Inc. All rights reserved.

Neoadjuvant Targeted Molecular Therapy in the setting of localized and locally advanced renal cell carcinoma has emerged as a strategy to render primary renal tumors amenable to planned surgical resection in settings where radical resection or nephron-sparing surgery was not thought to be safe or feasible. Presurgical tumor reduction has been demonstrated in a number of studies including a recently published randomized double-blind placebo-controlled study, and an expanding body of literature suggests benefit in select patients. Nonetheless, most reports are small phase II clinical trials or retrospective reports. Thus, large randomized clinical trial data are not present to support this approach, and guidelines for use of presurgical therapy have not been promulgated. The advent of immunomodulation through checkpoint inhibition represents an exciting horizon for neoadjuvant strategies. This article reviews the current status and future prospects of neoadjuvant therapy in nonmetastatic renal cell carcinoma.